Preparation of stable solutions of halogenated acetylcholin salts



Patented Apr. 18, 1933 UNITED STATES GUSTAV]! ROY, F BELLEVUE (SEINE ETOISE), FRANCE PREPARATION OF STABLE SOLUTIONS O]! HALOGENATEDACETYLGHOLIN SALTS Ho Drawing. Application flied December 2, 1930,Serial No. 499,539, and in Great Britain January 18, 1980.

Remedies which cannot be taken b the mouth are administered in the form0 sub cutaneous injections. The subcutaneous injection ofmanytherapeutical agents, however, causes painful and sometimesdangerous reactions, irritations, fever, or even mortification of thetissue. This prevents the use in therapeutics of many compounds whichcannot be taken by the mouth, and

l) which would be otherwise beneficial.

It follows that it is not sufiicient for a therapeutic agent whichcannot be taken bythe mouth to be eifective against disease, it mustalso be capable of beingtolerated y the patient, without objectionableafter effects, when administered in the form of subcutaneous injections.

Acetylcholin salts are the most powerful vasodilatating agents knownactually (see go Dale J our. Pharm. and Exp. Therap. vol. V1 p. 147(1914) and Jour. Physiology vol. 48 p. 111 (1914)). These salts are usedwith ood results in numerous accidents caused y hypertension:restrictive arteritis of the limbs (Raynauds disease), spasms of variouskinds (cerebral, retinian, auricular) neuro-vegetative troubles(hypovagotony). They are also very useful to oppose the perspiration oftuberculosis patients. The :0 treatment tt'all these diseases must beperformed by injection, which explains the utility of providin doctorswith a ready-made stable and sterihzable solution. Now, acetylcholinsalts, and specially the halo enated as salts, are very unstable inpresence 0 water, particularly at temperatures above normal. Applicantsinvention is based on the fact that the solutions of these saltspolyalcohols incompletely esterified withacetic acid are stable even atthe temperature to which they must be raised for sterilization and thatthey are tolerated b the livin human body without objectionab c after eacts.

It is known that acetylcholin salts, and 4 particularly halogenatedacetylcholin salts are ve unstable in (presence of moisture, particuarly at a raise temperature (see, for example, Fraenkeli ArzneimittelSynthese, 6th Ld. p. 336%. This is a ve objectionable feature wliic hasprevents hitherto the preparation of sterilized solutions suitable orbeing injected.

I have found that halogenated acetylcholin salts are soluble inpolyalcohols incompletely esterified with acetic acid, such as, for example, ethylene glycol monoacetin or glycerine mono or diacetin, and thatthe solutions so obtained can be sterilized, and preserved without anyalteration, of their physiological properties.

It might have been expected that the ethers produced by the partialetherification of the polyalcohols would cause painful reactions, oreven mortification of the tissues, when injected subcutaneously. I havefound, on the contrary, that these compounds are erfectly tolerated bypatients, so that no o jection arises to their use for intramuscularinjec tions. 7

Example-42.5 rammes acetylcholin bromide are dissolv in a mixture 0glycerin monoand di-aeetin, containing 60 per cent of the formercompound and 40 per cent of the latter, such a quantity of the mixturebeing taken that the volume of the solution obtained is 100 cc.

The solution is distributed in ampullee of /2 or 1 cc. which are sealedin the usual way and sterilized by heating in an autoclave.

The sterilized solution is as active as the initial solution, and it hasexcellent stability and preserving capability.

What I claim and desire to secure by Letters Patent is 1. A process forstabilizin and preserving halogenated acet lcholin sats without anyalteration of their physiolo 'cal properties, consisting in dissolving te halogenated acetylcholin salts in a polyalcohol incompletelyesterified with acetic acid.

2. A process for stabilizing and preserving halogenated acetylcholinsalts without any alteration of their physiological properties,consisting in dissolving the halogenated acetylcholin salts in ethyleneglycol monoacetin. V

3. A process for stabilizing and preserving halogenated acetylcholinsalts without any alteration of their physiological properties,consisting in disso ving the halogenatedoetscetylcholin salts inglycerine monoa 1n.

4. A process for stabilizing and preserving halogenated acetylcholinsalts without any alteration of their hysiological properties,consisting in disso ving the halogenated acetylcholin salts in glyoerinediaoetin.

5. As new composition of matter, a polyalcohol incompletely, esterifiedwith acetic acid, containing a halogenated acetylcholin salt in solutionand havin the property that it is stable and can be steri ized andpreserved without any alteration of the physiological prloprties of thehalogenated acetylcholin sa t.

6. As new composition of matter ethylene glycol mono-acetm containing ahai nated aeetylcholin salt in solution and having the. property that itis stable and can be stem ized and preserved without any alteration ofthe physiological properties of the halogenated acetylcholin salt.

7. As new composition of matter, glycerine mono-acetin containing ahalogenated acetylcholin salt in solution and having the propcity thatit is stable and can be sterilized and preserved without any alterationof the physiological roperties of the halogenated ace lcholin sa t.

8. As new composition of matter, lycerine diaoetin containing ahalogenateg acetylcholin salt in solution and having the propert that itis stable and can be stenlized an preserved without any alteration ofthe physiological roperties of the halogenated aoetyl o in t. p

In testimony whereof I have signed my name to this specification.

ous'mvn nor.

CERTIFICATE or CORRECTION. Patent No. 1,904,696.

GUSTAVE ROY.

April 18, 1933.-

It is hereby certified that the above numbered pstentvwas erroneouslyissued.v

to the inventor said "Roy," whcreas said patent should have been issuedto "Societe Des Usines Chimiques Rhone-Poulcnc, of Paris, France, aBodycorporate of FI ancc as assignee of the entire interest in saidinvention, as shown by the records of assignments in this office; andthat the said Letters latcnt. should be read with this correctiontherein that the same may conform to thc rccord of the case in thePatent Office.

Signed and sealed this 23rd day of May, A. D. 1933.

llLlloon.

lsonll Actin Commissioner 0! Pate tsedoetscetylcholin salts in glycerinemonoa 1n.

4. A process for stabilizing and preserving halogenated acetylcholinsalts without any alteration of their hysiological properties,consisting in disso ving the halogenated acetylcholin salts in glyoerinediaoetin.

5. As new composition of matter, a polyalcohol incompletely, esterifiedwith acetic acid, containing a halogenated acetylcholin salt in solutionand havin the property that it is stable and can be steri ized andpreserved without any alteration of the physiological prloprties of thehalogenated acetylcholin sa t.

6. As new composition of matter ethylene glycol mono-acetm containing ahai nated aeetylcholin salt in solution and having the. property that itis stable and can be stem ized and preserved without any alteration ofthe physiological properties of the halogenated acetylcholin salt.

7. As new composition of matter, glycerine mono-acetin containing ahalogenated acetylcholin salt in solution and having the propcity thatit is stable and can be sterilized and preserved without any alterationof the physiological roperties of the halogenated ace lcholin sa t.

8. As new composition of matter, lycerine diaoetin containing ahalogenateg acetylcholin salt in solution and having the propert that itis stable and can be stenlized an preserved without any alteration ofthe physiological roperties of the halogenated aoetyl o in t. p

In testimony whereof I have signed my name to this specification.

ous'mvn nor.

CERTIFICATE or CORRECTION. Patent No. 1,904,696.

GUSTAVE ROY.

April 18, 1933.-

It is hereby certified that the above numbered pstentvwas erroneouslyissued.v

to the inventor said "Roy," whcreas said patent should have been issuedto "Societe Des Usines Chimiques Rhone-Poulcnc, of Paris, France, aBodycorporate of FI ancc as assignee of the entire interest in saidinvention, as shown by the records of assignments in this office; andthat the said Letters latcnt. should be read with this correctiontherein that the same may conform to thc rccord of the case in thePatent Office.

Signed and sealed this 23rd day of May, A. D. 1933.

llLlloon.

lsonll Actin Commissioner 0! Pate ts-

